Volume 73, Issue 5 p. 406-416
Pharmacokinetics and Drug Disposition

Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors

Carla B. Washington PhD

Carla B. Washington PhD

Department of Medicine, Division of Clinical Pharmacology, Stanford University Medical Center, Stanford

Departments of Medicine, Pharmacology, and Molecular Sciences, Johns Hopkins University, Baltimore

Departments of Laboratory Medicine, Biopharmaceutical Sciences, and Medicine, University of California, San Francisco

Statistical and Data Analysis Center/Harvard School of Public Health, Boston

Medical Service, San Francisco General Hospital, San Francisco

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Charles Flexner MD

Charles Flexner MD

Department of Medicine, Division of Clinical Pharmacology, Stanford University Medical Center, Stanford

Departments of Medicine, Pharmacology, and Molecular Sciences, Johns Hopkins University, Baltimore

Departments of Laboratory Medicine, Biopharmaceutical Sciences, and Medicine, University of California, San Francisco

Statistical and Data Analysis Center/Harvard School of Public Health, Boston

Medical Service, San Francisco General Hospital, San Francisco

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Lewis B. Sheiner MD

Lewis B. Sheiner MD

Department of Medicine, Division of Clinical Pharmacology, Stanford University Medical Center, Stanford

Departments of Medicine, Pharmacology, and Molecular Sciences, Johns Hopkins University, Baltimore

Departments of Laboratory Medicine, Biopharmaceutical Sciences, and Medicine, University of California, San Francisco

Statistical and Data Analysis Center/Harvard School of Public Health, Boston

Medical Service, San Francisco General Hospital, San Francisco

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Susan L. Rosenkranz PhD

Susan L. Rosenkranz PhD

Department of Medicine, Division of Clinical Pharmacology, Stanford University Medical Center, Stanford

Departments of Medicine, Pharmacology, and Molecular Sciences, Johns Hopkins University, Baltimore

Departments of Laboratory Medicine, Biopharmaceutical Sciences, and Medicine, University of California, San Francisco

Statistical and Data Analysis Center/Harvard School of Public Health, Boston

Medical Service, San Francisco General Hospital, San Francisco

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Yoninah Segal MS

Yoninah Segal MS

Department of Medicine, Division of Clinical Pharmacology, Stanford University Medical Center, Stanford

Departments of Medicine, Pharmacology, and Molecular Sciences, Johns Hopkins University, Baltimore

Departments of Laboratory Medicine, Biopharmaceutical Sciences, and Medicine, University of California, San Francisco

Statistical and Data Analysis Center/Harvard School of Public Health, Boston

Medical Service, San Francisco General Hospital, San Francisco

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Judith A. Aberg MD

Judith A. Aberg MD

Department of Medicine, Division of Clinical Pharmacology, Stanford University Medical Center, Stanford

Departments of Medicine, Pharmacology, and Molecular Sciences, Johns Hopkins University, Baltimore

Departments of Laboratory Medicine, Biopharmaceutical Sciences, and Medicine, University of California, San Francisco

Statistical and Data Analysis Center/Harvard School of Public Health, Boston

Medical Service, San Francisco General Hospital, San Francisco

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Terrence F. Blaschke MD

Corresponding Author

Terrence F. Blaschke MD

Department of Medicine, Division of Clinical Pharmacology, Stanford University Medical Center, Stanford

Departments of Medicine, Pharmacology, and Molecular Sciences, Johns Hopkins University, Baltimore

Departments of Laboratory Medicine, Biopharmaceutical Sciences, and Medicine, University of California, San Francisco

Statistical and Data Analysis Center/Harvard School of Public Health, Boston

Medical Service, San Francisco General Hospital, San Francisco

Stanford University Medical Center, Division of Clinical Pharmacology, SUMC S-009, Stanford, CA 94305-5130, USA. E-mail: [email protected]Search for more papers by this author
First published: 17 May 2003
Citations: 3

Abstract

Objective

The aim of this study was to determine whether pharmacokinetic interactions between the protease inhibitors saquinavir soft gel, nelfinavir, and ritonavir are affected by the timing of administration.

Study design

We used an open-label, 6-period, incomplete Latin square crossover study in 18 human immunodeficiency virus–negative subjects. Each received single oral doses of 2 of the 3 protease inhibitors during each of 6 periods. Single doses were given either simultaneously or separated by 4 hours. The order of the periods was balanced, and periods were separated by 2 days. We measured protease inhibitor concentrations over a 24-hour period by HPLC and estimated pharmacokinetic parameters by noncompartmental methods.

Results

Median saquinavir area under the curve (AUC) increased by 62-fold when ritonavir was coadministered, by 50-fold when ritonavir was given 4 hours earlier, and by 16-fold when saquinavir preceded ritonavir by 4 hours. Saquinavir AUC increased by 7-fold when nelfinavir was coadministered. Nelfinavir AUC increased by 2.5-fold with coadministration of ritonavir and by 1.8- and 2.1-fold when ritonavir was administered before nelfinavir and after nelfinavir, respectively. Ritonavir AUCs were unaffected by coadministration of the other drugs. The effect of ritonavir on the kinetics of saquinavir persisted for at least 48 hours after a single dose of ritonavir, suggesting the possibility of metabolic intermediates that form inhibitory complexes.

Conclusion

Except for saquinavir followed by ritonavir, there is little difference in protease inhibitor exposure for simultaneous or staggered doses. The persistent effect of ritonavir suggests the possibility that lower doses and longer dosing intervals might be effective when ritonavir is used to boost concentrations of other protease inhibitors.

Clinical Pharmacology & Therapeutics (2003) 73, 406–416; doi: 10.1016/S0009-9236(03)00006-7